4-54263664-C-T

Variant names:

• chr4-54263664-C-T
• rs55947416
• NM_006206.6:c.368-3C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_006206.6(PDGFRA):​c.368-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0629 in 1,612,354 control chromosomes in the GnomAD database, including 3,637 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (226 hom., cov: 32)
  • Exomes 𝑓: 0.065 (3411 hom.)
• Consequence: PDGFRA NM_006206.6 splice_region, intron
• Scores: Splicing: ADA: 0.02828
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.39
• Publications: 13 publications found

Genes affected

PDGFRA (HGNC:8803): (platelet derived growth factor receptor alpha) This gene encodes a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor family. These growth factors are mitogens for cells of mesenchymal origin. The identity of the growth factor bound to a receptor monomer determines whether the functional receptor is a homodimer or a heterodimer, composed of both platelet-derived growth factor receptor alpha and beta polypeptides. Studies suggest that this gene plays a role in organ development, wound healing, and tumor progression. Mutations in this gene have been associated with idiopathic hypereosinophilic syndrome, somatic and familial gastrointestinal stromal tumors, and a variety of other cancers. [provided by RefSeq, Mar 2012]

PDGFRA Gene-Disease associations (from GenCC):

• gastrointestinal stromal tumor

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• polyps, multiple and recurrent inflammatory fibroid, gastrointestinal

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• isolated cleft palate

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000282278 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.21).
• BP6: Variant 4-54263664-C-T is Benign according to our data. Variant chr4-54263664-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0692 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDGFRA	NM_006206.6	c.368-3C>T		splice_region_variant, intron_variant	Intron 3 of 22	ENST00000257290.10	NP_006197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDGFRA	ENST00000257290.10	c.368-3C>T		splice_region_variant, intron_variant	Intron 3 of 22	1	NM_006206.6	ENSP00000257290.5
ENSG00000282278	ENST00000507166.5	c.1018-11261C>T		intron_variant	Intron 12 of 23	2		ENSP00000423325.1

Frequencies

GnomAD3 genomes AF: 0.0461 AC: 7019 AN: 152126 Hom.: 226 Cov.: 32

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0423

Gnomad ASJ AF: 0.0332

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0406

Gnomad FIN AF: 0.0607

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0709

Gnomad OTH AF: 0.0436

GnomAD2 exomes AF: 0.0488 AC: 12265 AN: 251276 AF XY: 0.0504

Gnomad AFR exome AF: 0.0102

Gnomad AMR exome AF: 0.0246

Gnomad ASJ exome AF: 0.0348

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.0628

Gnomad NFE exome AF: 0.0684

Gnomad OTH exome AF: 0.0489

GnomAD4 exome AF: 0.0646 AC: 94328 AN: 1460110 Hom.: 3411 Cov.: 32 AF XY: 0.0644 AC XY: 46750 AN XY: 726448

African (AFR) AF: 0.00938 AC: 314 AN: 33470

American (AMR) AF: 0.0270 AC: 1209 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0347 AC: 907 AN: 26122

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39698

South Asian (SAS) AF: 0.0490 AC: 4228 AN: 86236

European-Finnish (FIN) AF: 0.0653 AC: 3487 AN: 53412

Middle Eastern (MID) AF: 0.0271 AC: 156 AN: 5764

European-Non Finnish (NFE) AF: 0.0726 AC: 80655 AN: 1110346

Other (OTH) AF: 0.0556 AC: 3358 AN: 60348

GnomAD4 genome AF: 0.0461 AC: 7015 AN: 152244 Hom.: 226 Cov.: 32 AF XY: 0.0455 AC XY: 3388 AN XY: 74440

African (AFR) AF: 0.0118 AC: 490 AN: 41550

American (AMR) AF: 0.0422 AC: 646 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0332 AC: 115 AN: 3466

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5182

South Asian (SAS) AF: 0.0406 AC: 196 AN: 4822

European-Finnish (FIN) AF: 0.0607 AC: 643 AN: 10596

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0709 AC: 4820 AN: 68014

Other (OTH) AF: 0.0427 AC: 90 AN: 2110

Alfa AF: 0.0608 Hom.: 268

Bravo AF: 0.0409

Asia WGS AF: 0.0190 AC: 67 AN: 3478

EpiCase AF: 0.0649

EpiControl AF: 0.0636

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27884173, 20169295) -

Sep 24, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gastrointestinal stromal tumor Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hereditary cancer-predisposing syndrome Benign:2

Sep 13, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Feb 06, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Idiopathic hypereosinophilic syndrome Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.21
CADD	Benign	12
DANN	Benign	0.93
PhyloP100		2.4
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.028
dbscSNV1_RF	Benign	0.046
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs55947416; hg19: chr4-55129831; COSMIC: COSV57265057; COSMIC: COSV57265057;